The mitochondrial enzymes monoamine oxidase (MAO) catalyze the oxidative deamination of a number of biogenic and xenobiotic amines and regulate the concentration of these amines in brain and peripheral tissues. This activity produces ammonia, aldehydes and hydrogen peroxide, which are agents with established or potential toxicity. In the brain MAO is active in both neurons and glial cells.
In 1968 Jonston discovered that MAO exists in two forms, termed MAO A and MAO B, with different substrate specificities and inhibitor sensitivities (Jonston, J. P., Biochem. Pharmacol., 1968, 17, 1285). Recently, different cDNA clones have been isolated from the human liver encoding the A and B forms of MAO. It has been shown that MAO A and MAO B differ in primary structure with about 70% homology (Bach, A. W. J., Johnson, D. L., Abell, C. W., Bembenek, M. E., Kwan, S-W., and Shih, J. C., Proc. Natl. Acad. Sci, USA, 85:4934-4938; Shih, J. C. Neuropharm., 1991, 4, 1).
In humans, MAO A is predominantly located in the outer mitochondrial membrane of aminergic neurons but also found in the gut and placenta, while MAO B is the form found exclusively in platelets and is the major form present in liver and glial cells. MAO A primarily metabolizes norepinephrine and serotonin, whereas MAO B preferentially oxidizes dopamine (Murphy, D. L., Garrick, N. A., Aulakh, C. S., and Cohen, R. M., J. Clin. Psychiat., 1984, 45, 37). Inhibition of MAO A prevents the metabolism of catecholamines leading to an increased level of norepinephrine in the adrenergic neurons. Selective MAO B inhibition leading to an increased level of dopamine would decrease the extrapyramidal side effects associated with other MAO inhibitors. This would potentially eliminate the possibility of exaggerated responses, including severe headaches, hypertension (possible hypertensive crisis), and cardiac arrhythmias caused by the intake of tyramine containing foods (Ilett, K. F., George, C. F., and Davies, D. S. Biochem. Pharmacol., 1980, 29, 2551).
In humans, where dopamine is predominantly metabolized by MAO B, inhibitors of this isozyme should have utility as an adjunct to L-dopa in the treatment of Parkinson's disease, as well as in the treatment of Alzheimer's disease as cognitive enhancers.
The clinical use of long-acting irreversible MAO inhibitors of the old generation was hampered by their hepatotoxic and hypertensive effects as mentioned above. This fact and the potential of new therapeutic uses for MAO inhibitors has caused a renewed effort in discovering reversible and selective inhibitors both of A and B type.
Two good examples of this effort are the MAO inhibitors described by Schoofs et al. in U.S. Pat. No. 4,971,995 and by Renaut et al. in Foreign Patent No. WO90/11997 containing an unsubstituted hydroquinone ring. A subsistuent on this ring, especially electron withdrawing, provides an extended conjugated system with either of the oxygens on that ring. This can interact better with the flavin portion on the enzymatic active site. Furthermore it provides an extra interaction point with this site which increases both activity and selectivity between the two enzymes MAO A and MAO B.
It is an objective of this invention to provide compounds possessing the valuable pharmacological capability of inhibiting monoamine oxidases, and monoamine oxidase B in particular. It is a further objective of the present invention to provide methods of treating neurological disorders including but not limited to memory disorders, cognitive dysfunction, dementia, dementia of the Alzheimer's type, Parkinson's syndrome, depression, hyperactive syndrome, schizophrenia, and changes in temperament.